First generation taxoid compounds such as paclitaxel (Taxol®) and docetaxel (Taxotere®) have gained prominence as some of the most efficacious anticancer drugs. See E. K. Rowinsky, Annual Review of Medicine 1997, 48, 353; M. Suffness, Taxol Science and Applications; CRC Press: New York, 1995.
However, these first-generation taxane anticancer drugs exhibit little efficacy in treating melanoma, pancreatic, gastric, brain and renal cancers. These limitations are at least, in part, due to multi-drug resistance (MDR) caused by overexpression of ABC cassette efflux pumps and the beta-III tubulin isoform.
Second generation taxoid compounds with orders of magnitude higher potency have also been developed. See U.S. Pat. Nos. 6,096,909, 6,100,411, 6,458,976, and 6,500,858 to I. Ojima; G. I. Georg, T. Chen, I. Ojima, and D. M. Vyas (Eds.), “Taxane Anticancer Agents: Basic Science and Current Status,” ACS Symp. Series 583; American Chemical Society, Washington, D.C., 1995); I. Ojima, et al, Bioorg. Med. Chem. Lett., 1999, 9, 3423-3428; I. Ojima, et al, J. Med. Chem., 1996, 39, 3889-3896; and I. Ojima, G. D. Vite, K.-H. Altmann (Eds.), “Anticancer Agents: Frontiers in Cancer Chemotherapy,” ACS Symp. Series 796, American Chemical Society, Washington, D.C., 2001.
While these and other second generation taxoids have shown a high degree of efficacy in the treatment of various forms of cancer, there is a continuing need for improving the activity and mode of action of these compounds. There is a particular need to improve the efficacy of taxoid compounds against multi-drug resistance (MDR) in the treatment of cancer. There is also a need for taxoid compounds having less acute side effects and higher metabolic stability.